The inability of current synthetic scaffold materials to direct osteogenic cells to proliferate, differentiate into osteoblasts, and produce sufficient quantities of bone tissue limits the development of synthetic scaffolds for bone grafting applications in crucial areas such as orthopaedic, dental, and craniofacial procedures. Our longterm goal is to create bio-inspired tissue-engineered constructs that promote bone formation and repair. As a first step toward this goal, the objective of this application is to engineer novel scaffolds with controlled architectures that present biomimetic ligands by exploiting phase separation and self-assembly properties of block copolymers and to evaluate the ability of these scaffolds to promote osteoblastic differentiation and bone formation. Our central hypothesis is that precise control of polymer block design through integration of "living" polymerizations and self-assembly at the supramolecular levels will lead to porous scaffolds with enhanced functionality. This hypothesis is based on our recent studies of polymer self-assembly and biomimetic surfaces that direct cell function. The rationale for this work is that these newly engineered matrices will enhance osteoblast activities and bone repair to overcome existing limitations associated with current synthetic scaffolds. Our multidisciplinary team is well prepared to undertake the proposed research based on our expertise in organic synthesis, polymer chemistry, cell-materials interactions, and tissue engineering. In Aim 1, novel synthetic strategies towards functionalized block copolymers coupled with self assembly properties of these copolymers at the molecular-scale and meso-scale will be exploited in order to engineer scaffolds. In Aim 2, the second generation of scaffolds incorporating multiple functionalities including fibronectin-mimetic ligands to promote enhanced osteoblast cell adhesion and differentiation as well as proteinresistant poly(ethylene glycol) coatings will be fabricated. Osteogenic cell adhesion, proliferation, and differentiation will be evaluated. In Aim 3, we will evaluate the ability of these engineered scaffolds to promote in vivo osteoblastic differentiation and bone formation in an ectopic site. This work is expected to yield the following outcomes. We will: (i) identify block copolymers and controlled foaming approaches that yield families of mesoporous (50-500 [unreadable]m pores) scaffolds of varying architectures (pore size, interconnectivity, and strut size, shape and separation);(ii) establish surface engineering strategies to render these materials protein adsorption-resistant while presenting controlled cell adhesive ligands;and (iii) demonstrate that these novel materials exhibit superior osteoblast cell adhesion and differentiation and promote in vivo bone formation compared to unmodified and conventional polymeric supports. Collectively, these studies will validate the proposed novel concepts towards high strength biomimetic scaffolds. Optimization of the mechanical properties of the newly developed scaffolds will be part of a future application submission.